Design and Synthesis of Some Novel Oxadiazole Derivatives and Evaluation of In Vivo Anti Inflammatory Activity Followed by Molecular Docking against Cox-II Enzyme

摘要

Oxadiazole is a versatile heterocyclic nucleus which attracted a wide attention of the medicinal chemists in search for new therapeutic molecules. Out of its possible isomers 1, 3, 4-oxadiazole was widely exploited for various applications as medicinal agents. The literature survey revealed that 1, 3, 4-oxadiazoles were reported to possess a wide range of pharmacological activities. The main aim and objective of the present research work was designed and synthesis of some novel 2, 5-disubstituted 1, 3, 4- oxadiazole derivatives and evaluation of in vivo anti inflammatory activity followed by molecular docking against COX II enzyme. Based on this, a new series of compounds had been planned to synthesize by reacting paraacetamidophenol, ethylchloroacetate, hydrazine monohydrate and various aromatic acids. In continuation of these research work on 2, 5-disubstituted 1, 3, 4-oxadiazole and above observation promoted to synthesize the title compounds AB1-AB8 with their potent biological activity. Molecular docking was performed to find out the binding affinity or molecular interaction energy (kcal/mol) of docked compounds. Lowest (negative value) energy of docked molecule indicated high binding affinity with the target protein. In silico molecular docking studies, the binding energies of the synthesized compounds were found to be AB1: -4.21; AB2: -5.21; AB3: -5.06; AB4: -3.96; AB5: -4.38; AB6: - 3.45; AB7: -4.25; AB8: -3.83 (k.cal/ml); standard drug diclofenac sodium: -3.15 (k.cal/ml) which indicated that the compound had high binding affinity towards the target protein cyclooxygenase with PDB id 6COX (COX II). Anti inflammatory activity of each synthesized compound was evaluated by carrageenan induced paw oedema method. The activity was studied at 100 mg/kg body weight and their responses were measured at 30, 60, 120 and 180 minute. The in vivo experimental data displayed that the compound AB2, AB3, AB5 and AB7 possessed very good anti inflammatory activity among the eight synthesized compounds and all the compounds exhibited highest activity at 120 min. The percent protection (%) of the synthesized compounds were found to be AB1: 19.63±0.0294, AB2: 44.19±0.031**, AB3: 42.73±0.0351**, AB4: 19.04±0.0828ns, AB5: 39.53±0.0216*, AB6: 18.91±0.0310, AB7: 35.43±0.0623*, AB8: 18.84±0.0935ns, standard drug diclofenac sodium (DFS): 49.67±0.0095** etc.